表达CD19嵌合抗原受体的T细胞治疗儿童和青年急性淋巴细胞白血病：1期剂量递增试验
T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial
该1期剂量递增试验连续入组21名1至30岁复发或难治急性淋巴细胞白血病或非霍奇金淋巴瘤患者，用11天工艺制备靶向CD19的嵌合抗原受体（CAR）T细胞，输注前给予氟达拉滨和环磷酰胺清淋。19人（90%）成功接受预定剂量，最大耐受剂量为每公斤1×10⁶个CAR-T细胞。所有毒性均可逆，3人（14%）出现4级细胞因子释放综合征；常见3级非血液学不良事件包括发热、低钾血症、发热性中性粒细胞减少。结果说明CD19-CAR T细胞治疗化疗耐药的B前体急性淋巴细胞白血病可行、安全并有强效抗白血病活性，且未出现长期B细胞缺乏。
为什么推荐给您：新细胞疗法在连续入组儿童中的规范化1期剂量递增试验，确定耐受剂量与可行性。
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摘要Abstract
BACKGROUND: Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells.
METHODS: This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 10(6) CAR-transduced T cells per kg (dose 1), 3 × 10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696.
FINDINGS: Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 10(6) CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients).
INTERPRETATION: CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur.
FUNDING: National Institutes of Health Intramural funds and St Baldrick's Foundation.